Nonfunctional MED12 gene linked to chemotherapy resistance

medwireNews: Research published in Cell shows that people with tumors that have a nonfunctional version of the mediator 12 (MED12) gene are resistant to drugs used to treat lung and colon cancer such as gefitinib.

The team made their discovery after screening a lung cancer cell line with a mutation normally susceptible to anaplastic lymphoma kinase (ALK) inhibitors and found that the loss of function of MED12 could be reversed by inhibiting transforming growth factor beta receptor (TGF-βR) signaling.

"We have shown that blocking this escape route restores sensitivity to the original drug, suggesting a way to treat patients that have undergone this type of drug resistance," suggested study author René Bernards (The Netherlands Cancer Institute, Amsterdam) in a press statement.

The researchers screened 24,000 short hairpin (sh)RNAs targeting 8000 human genes using cells from the lung cancer cell line to assess whether any of the gene products would allow growth of cancer cells in the presence of chemotherapy drugs.

They found that cells with nonfunctional MED12 were not only resistant to ALK inhibitors, but also to MAPK/ERK kinase (MEK) and to v-Raf murine sarcoma viral oncogene homolog B1 or BRAF inhibitors.

Bernards and colleagues discovered that the nonfunctional MED12 caused activation of TGF-βR signaling, which causes MEK activation and resistance to various chemotherapy drugs.

"We need to understand the mechanisms of drug resistance to effectively prevent it from occurring in the first place," said Bernards.

"We have identified a mechanism of drug resistance that is caused by the activation of a specific signaling pathway in cancer cells," he added.

However, the findings do provide some hope for cancer patients with this mutation, as inhibition of TGF-βR signaling in cells with nonfunctional MED12 restores chemotherapy responsiveness, notes the team.

In an accompanying preview article, Xing Guo (University of California San Diego, La Jolla, USA) and Xiao-Fan Wang (Duke University Medical Center, Durham, North Carolina, USA) caution that these results are from cancer cell lines, which may not be completely representative of an in vivo tumor.

"Careful validation with in vivo models will be needed to convert these exciting findings into effective weapons in the battle against cancer," they write.

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